Caveolin-1 in Lipoprotein Metabolism and Atherosclerosis.

描述（由申请人提供）：动脉粥样硬化并发症是西方社会发病率和死亡率的主要原因。低密度脂蛋白（LDL）衍生的胆固醇和炎症细胞在动脉壁上的积累是导致动脉粥样硬化的初始事件。然而，引发动脉粥样硬化的因素仍然知之甚少。我们最近的数据表明，其中一个因素可能是小窝蛋白-1 (Cav-1)，它是小窝的重要结构成分。小泡是50-100 nm的质膜瓶状内陷，Cav-1在包括动脉内皮在内的多种组织中对小泡的生物形成至关重要。生理上，小泡的丢失导致胆固醇稳态受损、胰岛素抵抗、一氧化氮生成（NO）以及心肺和血管功能缺陷。有趣的是，缺乏Cav-1的小鼠表现出对动脉粥样硬化的抵抗，尽管有明显的促动脉粥样硬化脂质谱，这表明Cav-1决定了血管壁的动脉粥样硬化易感性。我们最近证明了内皮细胞Cav-1在小鼠动脉粥样硬化进展中的关键作用。小鼠缺乏Cav-1和ApoE，但在双敲除背景下表达内皮特异性Cav-1 （ApoE-/- cav - 1rec）。在ApoE基因敲除背景下，基因消融Cav-1可抑制动脉粥样硬化的进展，而在内皮中重新表达Cav-1可促进病变扩张。可能涉及几种不同的机制，包括降低LDL对动脉壁的浸润，增加一氧化氮（NO）的产生，减少白细胞粘附分子的表达和减少动脉粥样硬化斑块中的单核细胞积聚。Cav-1和/或小泡控制所有这些事件的确切机制尚不清楚。因此，这项拨款提案的主要挑战是确定内皮特异性Cav-1控制动脉粥样硬化早期阶段和进展的分子机制。我们提出了三个目标。目的1：探讨Cav-1调控动脉壁脂蛋白转运和动脉内皮细胞脂质/脂蛋白代谢的分子机制。目的2：明确NO在Cav-1缺失小鼠动脉粥样硬化保护中的作用。目的3：确定体内Cav-1表达是否调节EC炎症反应和巨噬细胞动员。总之，这些目标的完成将有助于深入了解Cav-1/小泡调节脂蛋白代谢和动脉粥样硬化进展的基本调节机制。

DESCRIPTION (provided by applicant): Complications from atherosclerosis represent a major cause of morbidity and mortality in Western society. The accumulation of low-density lipoprotein (LDL)-derived cholesterol and inflammatory cells in the artery wall are the initiating events that cause atherosclerosis. However, the factors that underlie the initiation of atherosclerosis are still poorly understood. Our recent data suggest that one such factor may be caveolin-1 (Cav-1), an important structural component of caveolae. Caveolae are 50-100 nm flask-shaped invaginations of plasma membrane, and Cav-1 is essential for caveolae biogenesis in several tissues, including the arterial endothelium. Physiologically, the loss of caveolae results in impairment of cholesterol homeostasis, insulin resistance, nitric oxide production (NO), and defects in cardiopulmonary and vascular function. Interestingly, mice deficient in Cav-1 exhibit resistance to atherosclerosis despite a marked proatherogenic lipid profile, suggesting that Cav-1 determines the athero-susceptibility to the vessel wall. We recently demonstrated the critical role of endothelial Cav-1 during the progression of atherosclerosis in mice. Mice were generated lacking Cav-1 and ApoE but expressing endothelial-specific Cav-1 in the double knockout background (ApoE-/-Cav-1REC). Genetic ablation of Cav-1 on the ApoE knockout background inhibited the progression of atherosclerosis, while re-expression of Cav-1 in the endothelium promoted lesion expansion. Several different mechanism appear to be involved, including reduced LDL infiltration into the artery wall, increased production of nitric oxide (NO), reduced expression of leukocyte adhesion molecules and decreased monocyte accumulation in atherosclerotic plaques. The precise mechanisms by which Cav-1 and/or caveolae controls all of these events remains unknown. Thus, a major challenge of this grant proposal is to determine the molecular mechanism by which endothelial-specific Cav-1 controls the early stages and progression of atherosclerosis. We propose three aims. Aim 1: To investigate the molecular mechanism by which Cav-1 regulates lipoprotein trafficking in the artery wall and lipid/lipoprotein metabolism in arterial endothelial cells. Aim 2: To define the role of NO in the atheroprotection observed in Cav-1 null mice. Aim 3: To define whether Cav-1 expression regulates EC inflammatory response and macrophage mobilization in vivo. In summary completion of these aims will provide insight into fundamental regulatory mechanism by which Cav-1/caveolae regulates lipoprotein metabolism and the progression of atherosclerosis.